Thermal Stability Kinetics and Shelf Life Estimation of the Redox‐Active Therapeutic and Mimic of Superoxide Dismutase Enzyme, Mn(III) meso‐Tetrakis(N‐ethylpyridinium‐2‐yl)porphyrin Chloride (MnTE‐2‐PyPCl₅, BMX‐010)

2区 · 生物学

ArticleOA

作者: de Araujo, Bárbara C R ; da Nova Mussel, Wagner ; Yoshida, Maria Irene ; Maia, Clarissa G C ; Sebastião, Rita de Cássia O ; de Freitas-Marques, Maria B ; Rebouças, Júlio S ; da Costa, Israel F

Mn(III) meso‐tetrakis(N‐ethylpyridinium‐2‐yl)porphyrin chloride (MnTE‐2‐PyPCl5, BMX‐010, and AEOL10113) is among the most studied superoxide dismutase (SOD) mimics and redox‐active therapeutics, being currently tested as a drug candidate in a phase II clinical trial on atopic dermatitis and itch. The thermal stability of active pharmaceutical ingredients (API) is useful for estimating the expiration date and shelf life of pharmaceutical products under various storage and handling conditions. The thermal decomposition and kinetic parameters of MnTE‐2‐PyPCl5 were determined by thermogravimetry (TG) under nonisothermal and isothermal conditions. The first thermal degradation pathway affecting Mn‐porphyrin structural integrity and, thus, activity and bioavailability was associated with loss of ethyl chloride via N‐dealkylation reaction. The thermal stability kinetics of the N‐dealkylation process leading to MnTE‐2‐PyPCl5 decomposition was investigated by using isoconversional models and artificial neural network. The new multilayer perceptron (MLP) artificial neural network approach allowed the simultaneous study of ten solid‐state kinetic models and showed that MnTE‐2‐PyPCl5 degradation is better explained by a combination of various mechanisms, with major contributions from the contraction models R1 and R2. The calculated activation energy values from isothermal and nonisothermal data were about 90 kJ mol–1 on average and agreed with one another. According to the R1 modelling of the isothermal decomposition data, the estimated shelf life value for 10% decomposition (t90%) of MnTE‐2‐PyPCl5 at 25°C was approximately 17 years, which is consistent with the high solid‐state stability of the compound. These results represent the first study on the solid‐state decomposition kinetics of Mn(III) 2‐N‐alkylpyridylporphyrins, contributing to the development of this class of redox‐active therapeutics and SOD mimics and providing supporting data to protocols on purification, handling, storage, formulation, expiration date, and general use of these compounds.

2021-01-01·Journal of Inorganic Biochemistry2区 · 生物学

Reduction of peroxynitrite by some manganoporphyrins of AEOL series: DFT approach with dispersion correction and NBO analysis

2区 · 生物学

Article

作者: Choe, Sung-Jub ; Sin, Kye-Ryong ; Maeng, Tae-Won ; Ko, Sun-Gyong ; Kim, Chol-Jin ; Ri, Kum-Ryong

The AEOL series of manganoporphyrins (MnP; AEOL compounds were named by US Aeolus pharmaceuticals) designed as superoxide dismutase mimic are well-known for their powerful catalytic activity to neutralize reactive oxygen and nitrogen species. Reductive oxygen atom cleavage from peroxynitrite (ONOO^-) to form NO₂ in aqueous solution by some AEOL compounds (AEOL-10113, AEOL-10150, AEOL-11114 and AEOL-11203) was studied by DFT/M06-2X computations with D3 dispersion correction and gCP (geometrical counterpoise correction) for basis set superposition error. DFT computation showed that AEOL-10150 can form the most stable association complex {MnP^…OONO} among four AEOL models. AEOL-10150 complex with ONOO^- has the lowest deformation energy. In AEOL compounds and their association complexes with ONOO^-, Mn atom prefered the high spin state (S = 2) to the intermediate spin state (S = 1). Natural bond orbital analysis showed that electron transfer from the most negative oxygen atom in ONOO^- to Mn atom in MnP has the biggest interaction energy among all kinds of donor-acceptor interactions between ONOO^- and MnP.

2020-06-09·Blood Advances2区 · 医学

Mn porphyrins as a novel treatment targeting sickle cell NOXs to reverse and prevent acute vaso-occlusion in vivo

2区 · 医学

Article

作者: Estupinan, Rodolfo ; Zennadi, Rahima ; Thamilarasan, Madhan ; Batinic-Haberle, Ines

AbstractIn sickle cell disease (SCD), adhesion of sickle red blood cells (SSRBCs) and activated leukocytes in inflamed venules affects blood rheology, causing vaso-occlusive manifestations and vital reduction in microvascular blood flow. Recently, we found that NADPH oxidases (NOXs) create a vicious feedback loop within SSRBCs. This positive feedback loop mediates SSRBC adhesion to the endothelium. We show for the first time the therapeutic effectiveness of the redox-active manganese (Mn) porphyrins MnTnBuOE-2-PyP5+ (MnBuOE; BMX-001) and MnTE-2-PyP5+ (MnE; BMX-010, AEOL10113) to treat established vaso-occlusion in a humanized sickle mouse model of an acute vaso-occlusive crisis using intravital microscopy. These Mn porphyrins can suppress SSRBC NOX activity. Subcutaneous administration of only 1 dose of MnBuOE or MnE at 0.1 to 2 mg/kg after the inflammatory trigger of vaso-occlusion, or simultaneously, reversed and reduced leukocyte and SSRBC adhesion, diminished leukocyte rolling, restored blood flow, and increased survival rate. Furthermore, MnBuOE and MnE administered to sickle mice subcutaneously at 0.1 to 1 mg/kg for 28 days (except on weekends) did not exacerbate anemia, which seemed to be due to downregulation of both SSRBC reactive oxygen species production and exposure of the eryptotic marker phosphatidylserine. In addition, Mn porphyrins ameliorated leukocytosis, venous blood gases, endothelial activation, and organ oxidative damage. Our data suggest that Mn porphyrins, likely by repressing NOX-mediated adhesive function of SSRBCs and activated leukocytes, could represent a novel, safe therapeutic intervention to treat or prevent the establishment of acute pain crises. These NOX-targeted antioxidants merit further assessment in SCD clinical trials.

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适应症	最高研发状态	国家/地区	公司	日期
哮喘	药物发现	美国	Aeolus Pharmaceuticals, Inc.	-
1型糖尿病	药物发现	美国	Aeolus Pharmaceuticals, Inc.	-
肿瘤	药物发现	美国	Aeolus Pharmaceuticals, Inc.	-
再灌注损伤	药物发现	美国	Aeolus Pharmaceuticals, Inc.	-
成人呼吸窘迫综合征	药物发现	美国	Aeolus Pharmaceuticals, Inc.	-
脑卒中	药物发现	美国	Aeolus Pharmaceuticals, Inc.	-